What is the first‑line antibiotic regimen for an adult with uncomplicated cystitis, and how does management differ in pregnancy, in men, or in complicated cases?

First-Line Treatment for Uncomplicated Cystitis in Adult Women

Nitrofurantoin monohydrate/macrocrystals 100 mg twice daily for 5 days is the preferred first-line oral regimen for acute uncomplicated cystitis in otherwise healthy adult women. 1, 2

Rationale for Nitrofurantoin as First Choice

• Nitrofurantoin achieves clinical cure rates of 88–93% and bacteriologic cure rates of 81–92%, comparable to other standard regimens while maintaining minimal resistance patterns (generally <10% worldwide). 1, 2
• This agent causes minimal collateral damage to normal flora, reducing selection pressure for multidrug-resistant organisms (MRSA, VRE, C. difficile) compared with fluoroquinolones and broad-spectrum cephalosporins. 1
• The 5-day duration is required for optimal efficacy; shorter courses are inadequate. 2

Alternative First-Line Options (When Nitrofurantoin Cannot Be Used)

Trimethoprim-sulfamethoxazole (TMP-SMX) 160/800 mg twice daily for 3 days may be used only if:

• Local E. coli resistance is documented to be <20%, AND
• The patient has not received TMP-SMX within the preceding 3–6 months, AND
• The patient has not traveled internationally within the preceding 3–6 months. 1, 2

When organisms are susceptible, TMP-SMX achieves 90–100% clinical cure rates, but efficacy plummets to 41–54% against resistant strains, making treatment failure the expected outcome when resistance thresholds are exceeded. 1

Fosfomycin trometamol 3 g as a single oral dose provides:

• Clinical cure rates of 90–91% but lower microbiologic cure rates of 78–80%. 2
• Convenient single-dose administration, useful when adherence to multi-day regimens is doubtful. 1, 2
• Should be avoided if early pyelonephritis is suspected due to lower tissue penetration. 2

Pivmecillinam 400 mg twice daily for 3–5 days (available primarily in Europe):

• Maintains excellent activity with minimal resistance (<10%). 1
• Has slightly lower efficacy than nitrofurantoin or TMP-SMX. 2, 3

Reserve (Second-Line) Agents—Use Only When First-Line Options Are Contraindicated

Fluoroquinolones (ciprofloxacin 250 mg twice daily for 3 days or levofloxacin):

• Achieve bacteriologic eradication rates of 93–97%. 1, 2
• Should be reserved for pyelonephritis or complicated infections due to concerns about collateral damage, C. difficile risk, tendinopathy, and promoting resistance. 1, 2, 3

Oral β-lactams (cefdinir, cefaclor, cefpodoxime-proxetil, cephalexin) for 3–7 days:

• Demonstrate inferior efficacy and higher adverse-event rates compared with nitrofurantoin or TMP-SMX. 2, 3
• Should be used only when all first-line agents are contraindicated. 2, 3

Agents to Avoid Completely

• Amoxicillin or ampicillin alone should never be used empirically due to worldwide resistance exceeding 30%, resulting in poor therapeutic outcomes. 1, 2, 3

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Management Differences in Special Populations

Men with Uncomplicated Cystitis

Men require a 7-day course (not 3 days) of the selected antibiotic because short-course therapy effective in women is inadequate for men. 1

• TMP-SMX 160/800 mg twice daily for 7 days is the standard regimen when local resistance is <20%. 1
• Nitrofurantoin 100 mg twice daily for 7 days is an alternative. 1
• Avoid amoxicillin, ampicillin, and β-lactams due to very high resistance rates and poor efficacy in male cystitis. 1

Pregnancy

Nitrofurantoin and fosfomycin remain appropriate throughout pregnancy, but specific caveats apply:

• Avoid TMP-SMX in the last trimester due to potential fetal risk (kernicterus). 1, 2
• Avoid trimethoprim alone in the first trimester due to neural tube defect concerns. 1
• Nitrofurantoin should be avoided near term (after 38 weeks) due to theoretical risk of hemolytic anemia in the newborn. 2
• Fosfomycin 3 g single dose is safe throughout pregnancy and offers convenient single-dose therapy. 1, 2

Complicated Cystitis (Structural/Functional Abnormalities, Immunosuppression, Recent Instrumentation)

Complicated UTIs require longer treatment duration (7–14 days) and often broader-spectrum coverage:

• Obtain urine culture before initiating therapy to guide definitive treatment. 2
• Fluoroquinolones (ciprofloxacin 500 mg twice daily or levofloxacin 750 mg once daily for 7–14 days) are appropriate empiric choices pending culture results. 1, 2
• Avoid nitrofurantoin and fosfomycin in complicated infections because they do not achieve adequate tissue levels outside the bladder. 2
• Consider parenteral therapy initially (ceftriaxone, aminoglycosides, or carbapenems) if systemic signs are present, then transition to oral therapy based on susceptibility. 4

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Diagnostic Considerations

• Urine culture is not routinely required for typical uncomplicated cystitis in otherwise healthy women; reserve it for atypical presentations, treatment failures, or recurrence within 2–4 weeks. 2
• Diagnosis is based on dysuria, urinary frequency, urgency, or suprapubic tenderness without fever, flank pain, or other signs of pyelonephritis. 2

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Critical Resistance Thresholds and Prescribing Pitfalls

When to Avoid TMP-SMX

• Do not use TMP-SMX empirically when local E. coli resistance exceeds 20%, because treatment failures outweigh benefits at this threshold. 1, 2
• Avoid TMP-SMX in patients with recent exposure (within 3–6 months) or recent international travel (within 3–6 months), as these factors independently predict resistance. 1
• Hospital antibiograms overestimate community resistance rates; use outpatient surveillance data when available. 1

Renal Function Assessment

• If eGFR >30 mL/min → prescribe nitrofurantoin 100 mg twice daily for 5 days. 2
• If eGFR <30 mL/min → avoid nitrofurantoin; consider fosfomycin 3 g single dose or a fluoroquinolone. 2

Common Pitfalls to Avoid

• Using fluoroquinolones as first-line therapy despite high efficacy, which promotes resistance needed for serious infections. 1, 2, 3
• Prescribing the 3-day regimen in men, which is ineffective; men require 7 days. 1
• Relying on hospital antibiograms for community-acquired cystitis, which reflect complicated infections and overestimate resistance. 1
• Extending treatment beyond recommended durations, which increases adverse events by 5% per additional day without added benefit. 1